The dorsal lateral geniculate nucleus (dLGN) serves as the primary thalamic relay for the transfer of retinal information to primary visual cortex. In addition to sensory signaling, thalamocortical circuits are involved in alterations of behavioral states (e.g., sleep/wake, attention, arousal), and certain pathophysiological conditions such as generalized absence epilepsy. The gating properties of thalamic nuclei, including the dLGN, result from the concerted integration of the intrinsic properties of thalamic neurons, synaptic organization, activity of afferent pathways, and impinging influence of neuromodulators. Growing evidence indicates the information transfer through the dLGN is a dynamic process and not a simple relay. Our long-range goals are to understand how these different processes influence thalamocortical circuits, and ultimately gain insight into how visual information is processed. Understanding these processes in the "normal" state should provide insight to potential abnormalities that may give rise to pathological conditions that disrupt visual processing. The proposed studies will focus on two major influences that can regulate thalamocortical gating: neuropeptides and inhibitory mechanisms. The thalamus receives rich peptidergic innervation from brainstem, neocortical and thalamic neurons. During the previous grant cycle, we identified a number of peptides that significantly alter thalamic neuron excitability. In this proposal we will determine the influence of these specific neuropeptides (vasoactive intestinal peptide (VIP), substance P (SP), and cholecystokinin (CCK)) on synaptic transmission in thalamocortical circuits. We hypothesize that these peptides serve as endogenous neuromodulators that are released in an activity-dependent manner and ultimately produce long-lasting changes in thalamic gating. Our proposed experiments will unravel the complexity of peptidergic actions in this system, and provide an understanding on the roles of neuropeptides on thalamic gating. The second thrust of our proposal focuses on an often-overlooked component in the thalamocortical circuit, namely intrinsic inhibitory mechanisms;we will investigate the role of inhibition on sensory information processing. Thalamic interneurons are intriguing in that they give rise to traditional axonal outputs, but also have presynaptic dendrites that spatially overlap with retinal inputs onto dLGN relay neurons. We can selectively manipulate the output of these presynaptic dendrites;however, their influences on retinogeniculate transmission are poorly understood. We will test our hypothesis that the presynaptic dendrites are stimulated in an activity-dependent manner and thus engage inhibitory mechanisms that would extend the dynamic range of retinal inputs in which thalamocortical neurons can respond to retinal input. In addition, we speculate that dendritic output of interneurons occur independent of somatic activity and thus, would serve as focal inhibitory influences, which would contrast with a distributed "global" influence of axonal outputs. Considering the integral role of inhibition in the regulation of neuronal excitability, and the potential long-lasting modulatory actions of neuropeptides on neuronal excitability, our findings will provide novel insights regarding the dynamics of thalamic gating. PUBLIC HEALTH RELEVANCE: The thalamus serves as a gateway for the transfer of sensory information from peripheral sense organs to the neocortex. Our proposed experiments are designed to identify basic cellular properties underlying the gating properties of thalamocortical circuits. These studies are critical not only for our understanding of visual processing, but an understanding of basic circuitry and physiology will provide a solid foundation for understanding pathological conditions involving the visual system.